Culture of human peripheral blood lymphocytes (PBL) in purified natural or recombinant interleukin-2 in the absence of exogenous antigen or mitogen causes the differentiation of nonlytic precursor cells into lymphokine-activated killers (LAK). A titration of purified Jurkat IL-2 (BRMP, FCRC, NIH) IL-2 showed that the relatively low concentration of 5 U/ml was optimal for LAK activation. The spectrum of target cells susceptible to LAK lysis in a 4-hour cheomium-51 release assay includes fresh NK-resistant tumor cells and trinitrophenyl (TNP) modified autologous PBL. Unmodified PBL are not lysed. Cold target inhibition studies indicated that LAK lysis of autologous TNP-PBL is totally inhibited by fresh tumor cells, and that tumor lysis is inhibited by TNP-PBL. Additionally, allogeneic tumors totally inhibit lysis of autologous tumor cells in other cold target studies. These results demonstrate that the lytic activity expressed by LAK is not HLA restricted, is not limited to tumor cells, and is "polyspecific" as indicated by the cross-reactive recognition of multiple target cell types in these cold target inhibition studies. The mechanism by which LAK effector cells mediate tumor cell destruction is unknown. Lysis occurs rapidly at 37 degrees, and 4 hours of incubation is optimal. The mechanism is neither an antibody-mediated cytotoxicity (ADCC) nor merely lectin-dependent cytotoxicity (LDCC). The report of successful adoptive therapy in mouse systems with LAK provides the basis for proposing that LAK is a biologically relevant system in which to further examine the mechanism and specificity of cell-mediated cytotoxicity.